The Chemistry and Biology of Ferroptosis

Abstract

Ferroptosis is a recently described form of cell death driven by iron-dependent lipid peroxidation. This type of cell death was first observed in response to treatment of tumor cells with a small-molecule chemical probe named erastin. Most subsequent advances in understanding the mechanisms governing ferroptosis involved the use of genetic screens and small-molecule probes. We describe herein the utility and limitations of chemical probes that have been used to analyze and perturb ferroptosis, as well as mechanistic studies of ferroptosis that benefitted from the use of these probes and genetic screens. We also suggest probes for ferroptosis and highlight mechanistic questions surrounding this form of cell death that will be a high priority for exploration in the future.

Keywords: ROS; cancer; cell death; chemical probe; cysteine; ferroptosis; glutathione; iron; lipid peroxidation; metabolism.

Figure 1.. The ferroptosis pathway and relevant chemical probes.

Molecules including cellular metabolites and protein factors that promote ferroptosis are in red, and those that prevent ferroptosis are in blue. Boxes show sets of chemical probes that inhibit system x_c⁻, GPX4, lipid peroxidation, and CoQ₁₀ production. Glu, glutamate; Cys, cysteine; GCL, glutamate-cysteine ligase; GSS, glutathione synthase; GSH, reduced glutathione; GSSG, oxidized glutathione; PUFA, polyunsaturated fatty acid; PL, phospholipid; LOX, lipoxygenase; R; free radicals; Et, ethyl. See Table for additional information.